The present invention relates to the use of aryl sulfonamide compounds, active as 5-HT6 receptor antagonists, in the treatment of obesity.
Obesity is a condition characterized in an increase in body fat content resulting in excess body weight above accepted norms. Obesity is the most important nutritional disorder in the western world and represents a major health problem in all industrialized countries. This disorder leads to increased mortality due to increased incidences of diseases such as cardiovascular disease, digestive disease, respiratory disease, cancer and NIDDM (type II diabetes). Searching for compounds, which reduce body weight has been going on for many decades. One line of research has been activation of serotonergic systems, either by direct activation of serotonin receptor subtypes or by inhibiting serotonin reuptake. The exact receptor subtype profile required is however not known.
Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of the peripheral and central nervous system, modulate a wide range of physiological and pathological functions, including anxiety, sleep regulation, aggression, feeding and depression. Multiple serotonin receptor subtypes have been identified and cloned. One of these, the 5-HT6 receptor, was cloned by several groups in 1993 (M Ruat, E Traiffort, J-M Arrang, J Tardivel-Lacombe, J Diaz, R Leurs, J-C Shwartz. Biochem. Biophys. Res. Commun. 1993, 193 (1) 268-276; M Sebben, H Ansanay, J Bockaert, A Dumuis, NeuroReport 5, 2553-2557 (1994).) This receptor is positively coupled to adenylyl cyclase and displays affinity for antidepressants such as clozapine. Recently, the effect of 5-HT6 antagonist and 5-HT6 antisense oligonucleotides to reduce food intake in rats has been reported (J C Bentley, C A Mardsen, A J Sleight and K C Fone Effect of 5-HT6 antagonist Ro 04-6790 on food consumption in rats traineds to a fixed feeding regime Br J Pharmac. 1999 Suppl 126 P66; J C Bentley, A J Sleight, C A Mardsen, K C F Fone 5-HT6 antisense oligonucleotide ICV affects rat performance in the water maze and feeding J Psychopharmacol Suppl A64 1997 255).
Aryl sulfonamide compounds have been disclosed as possessing 5-HT6 receptor activity and being useful in the treatment of CNS disorders (EP 815861). Further classes of aryl sulfonamide compounds with 5-HT6 receptor activity have been reported in WO 98/27081 and WO 99/42465. The compounds are believed to be of potential use in the treatment of certain CNS disorders.
The object of the present invention is to present an improved method of treatment of obesity. A further object is a new use of compounds for the manufacture of medicaments for obesity treatment.